Environmental triggers are evident in the etiology of many mental health disorders including highly heritable conditions such as schizophrenia. The identification of relevant environmental factors is critical for the development of treatment strategies and may ultimately help prevent disease onset in vulnerable individuals. We here propose to develop a mouse model to study the effects of postnatal stress on the expression of adult neurobiological and behavioral abnormalities. In the present proposal we will concentrate on effects of postnatal stress on the development and plasticity of cerebral cortex in male and female mice and associated behaviors. We hypothesize that perinatal stress can trigger profound neurobiological and cognitive abnormalities in adult mice which resemble human mental health disorders. This hypothesis is supported by current data, including preliminary results from our laboratory, showing sex dependent cerebral cortical and behavioral alterations, in adulthood, following early stress exposure. The objective of this proposal is to develop a mouse model for the study ofperinatat stress effects on adult cerebral cortical function that will allow us to characterize the ontogeny of the neurobiological changes leading to adult dysfunction in both sexes. Our long-term goal is to use this mouse model to study how interactions between environmental triggers and genetic vulnerabilities bring about altered brain structure and function akin to those seen in a variety of mental health disorders. For the present proposal we specifically aim to 1) determine if early postnatal stress differentially affects cortical morphogenesis, plasticity and cognitive behavior in male versus female BALB/CByJ mice; 2) determine the cellular substrate(s) of altered cortical ontogeny and plasticity in males compared to females, following postnatal stress; 3) test the hypothesis that the development of cholinergic and/or monoaminergic afferent neuromodulator projections is affected by postnatal temperature/separation stress and that such abnormal neuromodulatory projections, in turn, contribute to sex dependent alterations in plasticity and cognition in the adult. Such studies will lay the ground work for future, more detailed inquiries into the cellular, molecular and behavioral neurobiology associated with perinatal stress effects and their adult consequences. To date, knowledge of the fundamental neurobiological changes associated with the etiology of most major mental illness is incompletely, at best. The mouse model we propose to develop will, in future, contribute significantly to a better understanding of such etiologies.